Pharmaceutical Composition For The Treatment Of Pulmonary Arterial Hypertension

ABSTRACT

The present invention relates to high doses of macitentan, i.e. propylsulfamic acid [5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide or pharmaceutically acceptable salts, solvates, hydrates or morphological forms thereof, or of aprocitentan, for use in the treatment and/or prevention of pulmonary arterial hypertension (PAH). Moreover, the present invention relates to the use of high doses of macitentan, or of aprocitentan, for the manufacture of a medicament for the treatment and/or prevention of PAH, as well as to a method for the treatment and/or prevention of PAH comprising high doses of macitentan or of aprocitentan. Further, the present invention relates to a dosage regimen for the treatment and/or prevention of PAH as well as to a combination of macitentan, or of aprocitentan, with one or more phosphodiesterase type 5 (PDE5) inhibitors, prostacyclin analogues, prostacyclin receptor agonists or soluble guanylate cyclase stimulators. Therein, PAH is preferably mild or moderate PAH. Moreover, the present invention relates to a pharmaceutical composition for the treatment of PAH comprising a high dose of macitentan or of aprocitentan.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2019/086754, filed Dec. 20, 2019, which claims priority toInternational Patent Application No. PCT/EP2018/086724, filed Dec. 21,2018, International Patent Application No. PCT/EP2019/051830, filed Jan.25, 2019, International Patent Application No. PCT/EP2019/060151, filedApr. 18, 2019, International Patent Application No. PCT/EP2019/066494,filed Jun. 21, 2019, and International Patent Application No.PCT/EP2019/067186, filed Jun. 27, 2019, all disclosures of which areincorporated herein by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to high doses of macitentan (INN), i.e.propylsulfamic acid[5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amideor pharmaceutically acceptable salts, solvates, hydrates ormorphological forms thereof for use in the treatment and/or preventionof pulmonary arterial hypertension (PAH). Moreover, the presentinvention relates to the use of high doses of macitentan for themanufacture of a medicament for the treatment and/or prevention of PAH,as well as to a method for the treatment and/or prevention of PAHcomprising administering high doses of macitentan to a patient. Further,the present invention relates to a dosage regimen for the treatmentand/or prevention of PAH as well as to a combination of macitentan withone or more phosphodiesterase type 5 (PDE5) inhibitors, prostacyclinanalogues, prostacyclin receptor agonists or soluble guanylate cyclasestimulators. Therein, PAH is preferably mild or moderate PAH. Moreover,the present invention relates to a pharmaceutical composition for thetreatment of PAH comprising a high dose of macitentan.

BACKGROUND

Pulmonary hypertension (PH) was reported for the first time in 1891 whenthe autopsy of a patient with sudden death revealed right ventricularhypertrophy and pulmonary artery sclerosis without any apparent cause.Pulmonary arterial hypertension (PAH) is a subgroup of PH and it is aprogressive disease with elevated pulmonary vascular resistance (PVR) asthe basic cause for increased right ventricular afterload andhypertrophy, which eventually proceeds to right ventricular dilatationand failure, and premature death. PH is clinically classified into fivegroups according to the World Health Organization (WHO) classification:pulmonary arterial hypertension (PAH) (group 1), PH related to leftheart disease (group 2), PH due to lung disease and/or hypoxia (group3), chronic thromboembolic PH and other pulmonary artery obstructions(group 4), and PH with unclear and/or multifactorial mechanisms (group5) (Roger Hullin, Cardiovascular Medicine (2018), 21(7-8):195-199;Simonneau et al., Haemodynamic definitions and updated clinicalclassification of pulmonary hypertension. Eur. Respir. J. (2018), Dec.13. pii: 1801913. doi: 10.1183/13993003.01913-2018. [Epub ahead ofprint]).

The present invention focuses on PAH which is haemodynamicallycharacterised by the presence of a mean pulmonary artery pressure(PAP)>20 mm Hg, a pulmonary artery wedge pressure (PAWP)≤15 mm Hg and aPVR of equal to or more than (>) 3 Wood units, alternatively >2 Woodunits, all measured at rest.

In particular, the present invention focuses on PAH which ishaemodynamically characterised by the presence of a mean pulmonaryartery pressure (PAP)≥25 mm Hg, a pulmonary artery wedge pressure(PAWP)≤15 mm Hg and a PVR of equal to or more than (>) 3 Wood units,alternatively >2 Wood units, all measured at rest.

The pathophysiology of PAH is characterised by an imbalance betweenmolecules mediating vasoconstriction (e.g., endothelin or thromboxane)and/or molecules mediating vasodilation (e.g., prostacyclin and nitricoxide). Furthermore, mitogenic effects of these molecules, with specificpathomorphological changes in the pulmonary circulation are involved indisease progression.

Currently available compounds approved for specific treatment of PAH arein three different groups: a) endothelin receptor antagonists, b)phosphodiesterase type 5 inhibitors (PDE5 is) and soluble guanylatecyclase stimulators, and c) molecules interfering with the prostacyclinpathway. Treatment with these compounds in combination with generalmeasures has increased 3-year survival after first diagnosis ofidiopathic PAH from 48% in the 1980s to 74% in the last two decades, asshown in the REVEAL registry (Benza et al., An evaluation of long-termsurvival from time of diagnosis in pulmonary arterial hypertension fromthe REVEAL Registry. CHEST (2012), 142(2), 448-456; and CHEST (2012),141(2):354-362).

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a medication and/ortreatment regimen for pulmonary arterial hypertension (PAH). Inparticular it is an object of the present invention to provide amedication and/or treatment regimen for the treatment of mild ormoderate PAH. It is a further object of the present invention to providea combination medication and/or treatment for PAH.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a dose-response curve showing the change in hemoglobin (HGB)in function of the dose of macitentan administered to a human.

DETAILED DESCRIPTION

The present inventors have recognized that, despite fears of clinicallyrelevant hemoglobin decreases, blood pressure decreases and/or edema orfluid retention increases, it is possible and safe and effective totreat PAH patients with high doses of macitentan. In particular, it ispossible to decrease the progress of the disease, or even to improve thestatus of the disease.

In the present invention, macitentan is defined as propylsulfamic acid[5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl]-amide,i.e. a compound of formula (I)

or a pharmaceutically acceptable salt, solvate, hydrate or morphologicalform thereof.

Macitentan is an endothelin receptor antagonist (ERA) that acts as anantagonist of two endothelin (ET) receptor subtypes, ET_(A) and ET_(B)(Kholdani et al, Macitentan for the treatment of pulmonary arterialhypertension. Vasc. Health Risk Manag. (2014), 10, 665-673). Itshalf-life in humans is about 16 hours and steady state is reached by thethird day of administration (Bruderer et al., Absorption, distribution,metabolism, and excretion of macitentan, a dual endothelin receptorantagonist, in humans. Xenobiotica (2012), 42(9), 901-910). It isabsorbed slowly into the plasma (Sidharta et al., Macitentan:entry-into-humans study with a new endothelin receptor antagonist. Eur.J. Clin. Pharmacol. (2011), 67, 977-984). Macitentan dealkylates intothe active metabolite ACT-132577, which reaches its peak plasmaconcentration about 30 hours after the first dose is administered, andit has a half-life of approximately 48 hours. Although ACT-132577 has alower affinity for the ET receptors than its parent compound (Iglarz etal., Pharmacology of macitentan, an orally active tissue-targeting dualendothelin receptor antagonist. J. Pharmacol. Exp. Ther. (2008), 327(3),736-745), it maintains higher plasma concentrations than macitentan.Both compounds can be excreted from the body through the urine or feces.

It has previously been reported that the maximal or near-maximal effectof macitentan in rats is 10 mg/kg. (European Medicines Agency, EuropeanPublic Assessment Report for Opsumit, Procedure No. EMEA/H/C/002697/0000(2013) at 20 (“EMA Assessment Report”)). It has also previously beenreported that the maximal effective dose of macitentan in rats is 30mg/kg (Id.; e.g., Iglarz et al., Comparison of Pharmacological Activityof Macitentan and Bosentan in Preclinical Models of Systemic andPulmonary Hypertension. Life Sci. (2014), 118, 333-339; see alsoKunita-Takanezawa et al., Novel Dual Endothelin Receptor AntagonistMacitentan Reverses Severe Pulmonary Arterial Hypertension in Rats. J.Cardiovasc. Pharmacol. (2014), 64(5), 473-480).

In a multiple-ascending dose study evaluating 1 mg, 3 mg, 10 mg, and 30mg dosages of macitentan in healthy human subjects, plasma ET-1concentrations at steady-state showed a dose-dependent increase, with nofurther increase beyond the 10 mg oral dose, indicating blockade at thisdosage. (Id. at 40). The evaluators concluded that the 10 mg doseappeared to be close to the plateau of the pharmacological effect. (Id.at 48). The European Medicines Agency and the U.S. Food and DrugAdministration have approved the 10 mg daily oral dosage of macitentanfor the treatment of patients with pulmonary arterial hypertension.(EMA, Summary of Product Characteristics for Opsumit (Oct. 29, 2019) at2; FDA, Prescribing Information for Opsumit (April 2019) at 1).

In the following, several aspects of the invention will be explained.

One aspect of the present invention relates to macitentan for use in thetreatment and/or prevention of pulmonary arterial hypertension (PAH) inhuman, wherein the dosage of macitentan is more than 20 mg per day toequal to or less than 300 mg per day, for example, more than 20 mg perday to less than 250 mg per day. Preferably, the dosage is 25 mg to 200mg.

According to a more preferred aspect, these dosages are applied once aday.

In the present invention, PAH is defined as pulmonary arterialhypertension in human.

The present invention focuses on PAH which is haemodynamicallycharacterised by the presence of a mean pulmonary artery pressure(PAP)>20 mm Hg, a pulmonary artery wedge pressure (PAWP) 15 mm Hg and aPVR of equal to or more than (>) 3 Wood units, alternatively >2 Woodunits, all measured at rest. In addition to the above hemodynamiccharacterization, PAH is characterized clinically by the absence ofovert left-sided heart disease, severe lung disease, or known chronicthromboembolic disease.

In particular, the invention's focus is on PAH is characterizedhemodynamically by a right heart catheterization as:

-   -   Mean pulmonary artery pressure (mPAP)≥25 mm Hg    -   Pulmonary occlusion wedge pressure (PAWP)≤15 mm Hg    -   Pulmonary vascular resistance equal to or more than (>) 3 Wood        Units, alternatively >2 Wood units.

In addition to the above hemodynamic characterization, PAH ischaracterized clinically by the absence of overt left-sided heartdisease, severe lung disease, or known chronic thromboembolic disease.

As described above-macitentan is currently administered as 10 mg oraldose once a day. However, with the present invention it is suggested toadminister a high dosage of macitentan in order to improve the diseasestatus, prevent the occurrence of disease worsening, improve orstabilize the WHO functional class and improve long-term survival and/ordecrease hospitalization rate. Advantageously, if for instance comparedto bosentan, there are fewer to no side effects on liver function and noor insignificant hepatotoxicity.

Further advantages are no further clinically relevant decrease inhemoglobin, no further clinically relevant decrease in blood pressureand/or no further clinically relevant increase in edema/fluid retention.

Another aspect of the present invention relates to macitentan for use inthe treatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a), wherein the PAH is mild or moderate PAH,preferably moderate PAH.

Surprisingly it has been found that in mild and moderate PAH, thedisease status could be improved or stabilized; in particular, the WHOfunctional class could be improved in mild and moderate patients.Functional capacity, as measured with a 6-minute walk test, could alsobe improved.

The term “mild PAH” approximately equates to WHO Functional Class I andII.

The term “moderate PAH” approximately equates to WHO Functional ClassIII.

In contrast thereto, WHO Functional Class IV equates to severe PAH.

The WHO Functional Classes (WHO FC) are commonly known and defined asfollows:

WHO FC I: No symptoms of pulmonary arterial hypertension with exerciseor at rest. It is rare for a patient to be diagnosed while still a classI. Patients that are being screened because of high risk factors fordeveloping PAH, such as patients with scleroderma or family history ofPAH, may rarely be diagnosed as class I. More often this classificationis used to describe patients who have demonstrated a substantialresponse to therapy who were once a class II or III but have improved toa class I.

WHO FC II: No symptoms at rest but uncomfortable, fatigued, or short ofbreath with normal activity such as climbing a flight of stairs, groceryshopping, or making the bed.

WHO FC III: Patients may not have symptoms at rest but normal activitiesare greatly limited by shortness of breath, fatigue, or near fainting.Patients in this class have a difficult time doing normal chores aroundthe house and have to take breaks while doing activities of dailyliving.

WHO FC IV: Symptoms at rest or severe symptoms with any activity.

Patients in this class may faint with activity or while bending overwith their heads lowered. Many patients in this class are also volumeoverloaded with edema in their feet and ankles from right heart failure.

A more detailed assessment for mild PAH is determined as follows:(dmild): Fulfilling at least 3 of the following criteria:

-   -   WHO FC I or II;    -   Six-minute walk distance (6MWD)>440 m;    -   B-type natriuretic peptide (BNP)<50 ng/L or N-terminal        pro-B-type natriuretic peptide (NT-proBNP)<300 ng/L; or RAP<8        mmg HG;    -   CI≥2.5 L/min/m² or SvO₂>65%;    -   and not fulfilling any of the (dsevere) criteria.

A more detailed assessment for severe PAH is determined as follows:(dsevere): Fulfilling at least two of the following features, includingCI or SvO₂:

-   -   WHO FC IV;    -   6MWD<165 meters;    -   BNP>300 ng/L or NT-proBNP >1400 ng/L; or RAP>14 mmg HG    -   CI<2.0 L/min/m² or SvO₂<60%.

A more detailed assessment for moderate PAH is determined as follows:(dmoderate) the aforementioned assessments of the (dmild) criteria andthe (dsevere) criteria do neither allow to classify the patient's PAH asmild PAH nor allow to classify the patient's PAH as severe PAH.

Preferably, the concentration of NT-proBNP, rather than theconcentration of BNP, will be determined and used to decide whether thepatient has mild, moderate or severe PAH according to the preceding moredetailed assessment definitions.

BNP is measured as follows: a plasma sample is collected and shippedfrozen (−20° C. or below) in a plastic EDTA tube and analyzed with animmunochemiluminometric assay (ICMA). The principles of this ICMA assayare as follows:

-   -   A commercially available kit (Triage® BNP test) with the        following 3 working solutions/suspensions is used:        -   S1a: paramagnetic particles coated with mouse omniclonal            anti-human BNP antibody suspended in TRIS buffered saline            solution (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq. solution),            with bovine serum albumin (BSA), 0.1% ProClin™ 300            (0.60-1.00% 2-methyl-4-isothiazolin-3-one and 2.10-2.80%            5-chloro-2-methyl-4-isothiazolin-3-one aq. solution) and            <0.1% sodium azide;        -   S1 b: purified mouse and goat IgG in Tris buffered saline            solution (150 mM NaCl, 50 mM Tris-HCl, pH 7.6 aq. solution),            with bovine serum albumin (BSA), 0.1% ProClin™ 300            (0.60-1.00% 2-methyl-4-isothiazolin-3-one and 2.10-2.80%            5-chloro-2-methyl-4-isothiazolin-3-one aq. solution) and            <0.1% sodium azide; and        -   S1c: mouse monoclonal anti-human BNP antibody-alkaline            phosphatase bovine conjugate in PBS buffered saline solution            (pH 7.4; 137 mmol/L NaCl, 2.7 mmol/L KCl, 10 mmol/L Na₂HPO₄            and 1.8 mmol/L KH₂PO₄), with bovine serum albumin (BSA),            0.1% ProClin™ 300 (0.60-1.00% 2-methyl-4-isothiazolin-3-one            and 2.10-2.80% 5-chloro-2-methyl-4-isothiazolin-3-one aq.            solution) and <0.1% sodium azide.    -   The blood sample (500 μL) is collected from the patient and        placed in a plastic blood draw tube containing K₂EDTA as an        anticoagulant. The blood sample should be mixed by gently        inverting the tube several times.    -   The suspension S1a and the solution S1c are placed in a reaction        vessel and 55 μL of the blood sample is added thereto.    -   After incubation in the reaction vessel, a magnetic field is        used to hold the materials bound to the solid phase and unbound        materials are washed away using the solution S1 b.    -   A chemiluminescent substrate, Lumi-Phos® 530 (Chemical Abstracts        Substance No. 146239-76-1), is then added into the reaction        vessel and light generated by the reaction is measured by a        luminometer. The resulting light is proportional to the BNP        concentration, thus allowing to determine the BNP concentration        in the sample.    -   To ensure accuracy of the ICMA assay results, the luminometer        should regularly be calibrated with commercially available        reference solutions.

NT-proBNP is measured as follows: a serum or plasma sample is collectedand shipped at ambient temperature if within 3 days of collection orfrozen in a red-top tube, after centrifugation, and analyzed with anelectrochemiluminescence immunoassay (ECLIA). The principles of thisECLIA assay are as follows:

-   -   A commercially available kit with the following 3 working        solutions/suspensions is used:        -   S1: A suspension (6.5 mL) of streptavidin-coated            microparticles (0.72 mg/mL) containing preservative;        -   S2: A solution (9 mL) of Anti-NT-proBNP-Ab-biotin,            containing Biotinylated monoclonal anti-NT-proBNP antibody            (mouse) (1.1 μg/mL), phosphate buffer 40 mmol/L, pH 5.8 and            preservative; and        -   S3: A solution (9 mL) of Anti-NT-proBNP-Ab-Ru(bpy),            containing a monoclonal NT-proBNP-specific antibody labeled            with the tris(2,2′-bipyridyl)ruthenium(II) complex (Ru(bpy))            (1.1 μg/mL), phosphate buffer 40 mmol/L, pH 5.8 and            preservative.    -   The sample (15 μL) is first incubated with the solutions S2 and        S3; the biotinylated monoclonal NT-proBNP-specific antibody and        the monoclonal NT-proBNP-specific antibody labeled with a        ruthenium complex form a sandwich complex.    -   A second incubation is then performed, whereby, after addition        of the suspension S1, the complex becomes bound to the solid        phase via interaction of biotin and streptavidin.    -   The reaction mixture is aspirated into the measuring cell where        the microparticles are magnetically captured onto the surface of        the electrode. Unbound substances are then removed. Application        of a voltage to the electrode then induces chemiluminescent        emission which is measured by a photomultiplier.    -   Results are determined based on a calibration curve using        commercially available reference solutions.

CI is measured as follows: CI reflects the flow of blood (liters/minute)through the heart, which is called cardiac output (CO), standardized tothe patient's body surface area (BSA); the CI is thus expressed inliters/minute/meter². A right heart catheterization (RHC) is a standardprocedure used to diagnose PAH. It is an invasive procedure during whicha catheter is inserted through a large vein and then the catheter isadvanced to the right side of the heart and then into the pulmonaryartery. There are different methods to measure the CI, but the mostcommon methods are Fick cardiac index method or Thermodilution cardiacindex method. These are standardized and well-established methods. Themost accepted method is the thermodilution method. According to thisinvention, the thermodilution (TD) method will be the specific methodused to measure CI. TD determines the CO based on how fast a set amountof fluids (typically at room temperature, i.e., 25° C.) moves from theright atrium [injected into the proximal port of the pulmonary artery(PA) catheter] to the PA (detected by a thermo-sensor close to the tipof the distal part of the PA catheter). An area under the curve (AUC) ofthe change in temperature is generated. This is to be repeated at least3 times, and then the average value will be calculated, but the valuesshould be within (+/−) 10-15% of each other for these measurements to bevalid. The curves should also be assessed to make sure the flow issmooth without sharp changes in the curve that may suggest erroneousinjections or measurements. Based on the average AUC obtained and thepatient's BSA, defined as follows

BSA=√[(height in cm×weight in kg)/3600]

the CI is calculated.

RAP is measured as follows: the RAP (occasionally referred to as mRAP,i.e. mean RAP) is also measured during the RHC procedure as outlinedabove for measuring the CI. There is a pressure sensor at the tip of thecatheter that is inserted in a vein that makes its way into the rightside of the heart. The sensor measures the pressure when the cathetertip is in the right atrium, and that measured pressure is the RAP. It isa single measurement.

SvO₂ is measured as follows: the SvO₂ is also measured during the RHCprocedure as outlined above for measuring the CI. When the catheter tipis in a central vein or the right atrium, blood is withdrawn and theoxygen ‘concentration’/‘content’ (partial pressure of oxygen in theblood) in that blood sample is analyzed using standard blood gasanalyzers/sensors; the % of oxygenation in that blood sample is theSvO₂. It is also a single measurement.

For more detailed assessment, mild and moderate PAH can be definedaccording to an algorithm which is based on the Registry to EvaluateEarly and Long-term PAH Diseases Management (REVEAL Registry). Thealgorithm may be described as comprising the following steps:

-   -   (i) Determination of the WHO Group I Subgroup of the patient and        assigning        -   +1 score for APAH-CTD (PAH associated with connective tissue            disease),        -   +2 scores for APAH-PoPH (PAH associated with porto-pulmonary            hypertension),        -   +2 scores for FPAH (familial PAH, which is currently            referred to heritable PAH);        -   0 score for any other subgroups of PAH;    -   (ii) Determination of demographics and comorbidities and        assigning        -   +1 score for renal insufficiency,        -   +2 scores for male age >60 years,        -   0 score for other patients;    -   (iii) Determination of the WHO Functional Class and assigning        -   −2 scores for WHO FC I        -   0 scores for WHO FC II        -   +1 score for WHO FG III        -   +2 scores for WHO FG IV    -   (iv) Determination of vital signs and assigning        -   +1 score for SBP (systolic systemic blood pressure)<110            mmHg,        -   +1 score for HR (heart rate) >92 BPM (beats per minute),        -   0 score for any other cases;    -   (v) Determination of the 6-minute walk distance and assigning        -   −1 score for ≥440 meters,        -   +1 score for <165 meters,        -   0 scores for any other cases;    -   (vi) Determination of BNP (brain natriuretic peptide) and        assigning        -   −2 scores for BNP<50 pg/mL,        -   +1 score for BNP>180 pg/mL,        -   0 score for BNP from 50 pg/mL to 180 pg/mL;    -   (vii) Determination of an echocardiogram and assigning        -   +1 score for pericardial effusion,        -   0 scores for any other cases;    -   (viii) Pulmonary function test and assigning        -   −1 score for % predicted DLCO≥80% (diffusing capacity of            lung for Carbon monoxide),        -   +1 score for % predicted DLCO≤32%,        -   0 scores for % predicted DLCO between 32% and 80%;    -   (ix) Right heart catherization and assigning        -   +1 score for RAP (mean right arterial pressure)>20 mm Hg            within 1 year,        -   +2 scores for PVR (pulmonary vascular resistance)>32 Wood            units,        -   0 scores for any other cases;    -   (x) Summarize the scores obtained in steps (i) to (ix) and add        the number 6;    -   (xi) mild PAH is assigned for a score from 1 to 7, and moderate        PAH is assigned for a score of 8 or 9.        In the above algorithm “+” means to add, “−” means to subtract.

A Wood Unit is the measure of a simplified system for measuringpulmonary vascular resistance (PVR) that uses increments of pressure.Measurement of PVR is made by subtracting pulmonary artery wedgepressure from the mean pulmonary arterial pressure and dividing bycardiac output in liters per minute.

Hence, mild PAH is associated with a score of 1-7, and moderate PAH isassociated with a score of 8 or 9.

For further definitions, it is expressly pointed to the ESC/ERSGuidelines, European Heart Journal (2016), 37, 67-119.

Hereditary transmission of PAH has been reported in approximately 6% to10% of patients with PAH; in 50% to 90% of these individuals, mutationsin BMPR2 (bone morphogenetic protein receptor type-2) have beenidentified. The mutations in BMPR2 in familial pulmonary arterialhypertension (FPAH) are characterized by genetic anticipation andincomplete penetrance. FPAH is also referred to as HPAH (hereditaryPAH). The phenotype is not expressed in all generations, but whenexpressed, occurs at an earlier age and is associated with more severeand rapidly progressive disease. Many other genetic mutations have beenidentified to be associated with familial (heritable) PAH, but these aremuch less common than the BMPR2 mutation (Morrell et al., Eur. Respir.J. (2018), Dec. 13. pii: 1801899. doi: 10.1183/13993003.01899-2018.[Epub ahead of print]).

In the present invention, APAH-CTD (PAH associated with connectivetissue disease) is characterized by PAH in someone who also has anautoimmune disease, also called connective tissue disease. The mostcommon connective tissue diseases that are associated with PAH arescleroderma (systemic sclerosis), Lupus (systemic lupuserythematosus/SLE), mixed connective tissue diseases and Sjogren'sdisease.

In the present invention, APAH-PoPH (PAH associated with porto-pulmonaryhypertension) is characterized by PAH that is associated with portalhypertension. Portal hypertension is defined as increased pressure inthe portal vein as evidenced by an increase in the gradient of pressurebetween the portal vein and the hepatic vein by more than 5 mm Hg (itbecomes clinically significant if the pressure gradient is 10 mm Hg).The portal vein carries blood from the gastrointestinal system to theliver. Although this happens more often in the presence of advancedliver disease causing the portal hypertension, porto-pulmonaryhypertension may happen in the absence of liver disease as long as thereis portal hypertension.

PAH associated with portal hypertension is commonly referred to as PoPH.This entity should not be confused with hepatopulmonary syndrome, whichis characterized by abnormal pulmonary vasodilation and hypoxaemia.However, overlaps between both conditions may occur. As implied by theterm, PoPH is associated with the presence of portal hypertension asdefined above, not necessarily with the presence of liver disease.However, as cirrhotic liver disease is by far the most common cause ofportal hypertension, PoPH is most frequently encountered in patientswith cirrhosis.

A complete diagnostic workup including a right heart catheterization(RHC) is required to assess disease severity, haemodynamic profile andother potential causes of PH, including lung disease, LHD or chronicthromboembolic disease (ESC/ERS Guidelines, European Heart Journal(2016), 37, 67-119).

In the present invention, renal insufficiency is characterized by aglomerular filtration rate (GFR) below 90 ml/min/1.73 m². The GFR isobtained by obtaining standardized creatinine blood concentration (SCr)from the patient and using the MDRD equation which is as follows:

GFR=175×SCr^(−1.154)×age^(−0.203)×(0.742 if female)×(1.21 if black)

The GFR obtained according to the equation above is expressed in mL/minper 1.73 m² body surface area. If the body surface area of the patientis different from 1.73 m², the value obtained for the GFR through theMDRD equation above should be converted accordingly.

Pericardial effusion is a collection of fluid around the heart.Normally, there should be a very thin, typically invisible to the normaleye, layer of fluid that acts as lubricant to prevent friction betweenthe heart and the pericardium (fibrinous layer surrounding andprotecting the heart). In the setting of advanced PH (as well as manyother diseases), that fluid builds up and forms a collection around theheart, defined as pericardial effusion. The presence of such an effusionportends poor prognosis as it signifies advanced PH and right heartdysfunction/failure.

DLCO is measured via pulmonary function tests. These tests are performedas described in Graham et al., 2017 ERS/ATS standards for single-breathcarbon monoxide uptake in the lung, Eur. Respir. J. (2017), 49, 1600016.

RHC is an invasive, typically, outpatient procedure that involvesinserting a catheter through a central vein and then passing it throughthe right sided heart chambers to reach the pulmonary artery. Differentmeasurements are taken during this procedure including pressures andblood flow termed cardiac output.

Another aspect of the present invention relates to macitentan for use inthe treatment and/or prevention of PAH according to aspect (a) or (b),wherein the dosage of macitentan is 60 to 90 mg per day. Preferably, thedosage is 65 to 85 mg per day, more preferably the dosage is 70 to 80 mgper day and most preferably the dosage is 75 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 60 to85 mg, from 60 to 80 mg, or from 60 to 75 mg per day. Also disclosed aredosages from 65 to 90 mg, or 65 to 75 mg per day. Further preferredranges are 72 to 78 mg per day. According to a more preferred aspect,these dosages are applied once a day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is 25 to 50 mg per day.Preferably, the dosage is 30 to 45 mg per day, more preferably 35 to 40mg per day and most preferably 37.5 mg per day. It is to be understoodthat each of the lower limits disclosed above may be combined with eachof the upper limits, i.e. the dosage could also be from 25 to 45 mg perday, or from 25 to 40 mg per day. Also disclosed are doses from 30 to 50mg, or 30 to 40 mg per day. Further preferred ranges are 36 to 39 mg perday. According to a more preferred aspect, these dosages are appliedonce a day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is 110 to 200 mg per day.Preferably, the dosage is 125 to 175 mg per day, more preferably 140 to160 mg per day and most preferably 150 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 110 to175 mg per day, from 110 to 160 mg per day or from 110 to 150 mg perday. Also disclosed are doses from 125 to 160 mg or 140 to 175 mg perday. Further preferred ranges are 145 to 155 mg per day. According to amore preferred aspect, these dosages are applied once a day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is 60 to 90 mg twice per day.Preferably, the dosage is 65 to 85 mg twice per day, more preferably 70to 80 mg twice per day and most preferably 75 mg twice per day. It is tobe understood that each of the lower limits disclosed above may becombined with each of the upper limits, i.e. the dosage could also befrom 60 to 85 mg twice per day, from 60 to 80 mg twice per day, or from60 to 75 mg twice per day. Also disclosed are dosages from 65 to 90 mgtwice per day, or 65 to 75 mg twice per day. Further preferred rangesare 72 to 78 mg twice per day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is 25 to 50 mg twice per day,preferably 30 to 45 mg twice per day, more preferably 35 to 40 mg twiceper day and most preferably 37.5 mg twice per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 25 to45 mg twice per day, or from 25 to 40 mg twice per day. Also disclosedare doses from 30 to 50 mg twice per day, or 30 to 40 mg twice per day.Further preferred ranges are 36 to 39 mg twice per day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is escalated from 10 mg per day,followed by 25 to 50 mg per day, preferably 37.5 mg per day, andoptionally followed by 60 to 90 mg per day, preferably 75 mg per day.Therein “followed by 25 to 50 mg per day” means preferably, the dosageis 30 to 45 mg per day, more preferably 35 to 40 mg per day and mostpreferably 37.5 mg per day. It is to be understood that each of thelower limits disclosed may be combined with each of the upper limits,i.e. the dosage could also be from 25 to 45 mg per day, or from 25 to 40mg per day. Also disclosed are doses from 30 to 50 mg, or 30 to 40 mgper day. Further preferred ranges are 36 to 39 mg per day. It is to beunderstood that any escalation to a higher dose may be followed byreturn to the lower dose in case the higher dose is not tolerated.

Moreover, the phrase “optionally followed by 60 to 90 mg per day” meanspreferably, the dosage is 65 to 85 mg per day, more preferably thedosage is 70 to 80 mg per day and most preferably the dosage is 75 mgper day. It is to be understood that each of the lower limits disclosedabove may be combined with each of the upper limits, i.e. the dosagecould also be from 60 to 85 mg, from 60 to 80 mg, or from 60 to 75 mgper day. Also disclosed are dosages from 65 to 90 mg, or 65 to 75 mg perday. Further preferred ranges are 72 to 78 mg per day. It is to beunderstood that any escalation to a higher dose may be followed byreturn to the lower dose in case the higher dose is not tolerated.

According to a more preferred aspect, these dosages are applied once aday.

At present, the dosage of macitentan for use in the treatment of PAH is10 mg per day. Patients obtaining this dosage may receive an immediatedose escalation to 37.5 mg per day, optionally followed by 75 mg perday.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is escalated from 10 mg per day,followed by 25 to 50 mg per day, preferably 37.5 mg per day, optionallyfollowed by 60 to 90 mg per day, preferably 75 mg per day, optionallyfollowed by 110 to 200 mg per day, preferably 150 mg per day.

The phrase “optionally followed by 110 to 200 mg per day” meanspreferably, the dosage is 125 to 175 mg per day, more preferably 140 to160 mg per day and most preferably 150 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 110 to175 mg per day, from 110 to 160 mg per day or from 110 to 150 mg perday. Also disclosed are doses from 125 to 160 mg or 140 to 175 mg perday. Further preferred ranges are 145 to 155 mg per day. According to amore preferred aspect, these dosages are applied once a day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is escalated from 10 mg per day,followed by 60 to 90 mg per day, preferably 75 mg once per day or 37.5mg twice a day.

The phrase “optionally followed by 60 to 90 mg per day” meanspreferably, the dosage is 65 to 85 mg per day, more preferably thedosage is 70 to 80 mg per day and most preferably the dosage is 75 mgper day. It is to be understood that each of the lower limits disclosedabove may be combined with each of the upper limits, i.e. the dosagecould also be from 60 to 85 mg, from 60 to 80 mg, or from 60 to 75 mgper day. Also disclosed are dosages from 65 to 90 mg, or 65 to 75 mg perday. Further preferred ranges are 72 to 78 mg per day. It is to beunderstood that any escalation to a higher dose may be followed byreturn to the lower dose in case the higher dose is not tolerated.

According to a more preferred aspect, these dosages are applied once aday.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (a) or(b), wherein the dosage of macitentan is escalated from 10 mg per day,followed by 60 to 90 mg per day, preferably 75 mg once per day or 37.5mg twice a day, optionally followed by 110 to 200 mg per day, preferably150 mg per day.

The phrase “optionally followed by 110 to 200 mg per day” meanspreferably, the dosage is 125 to 175 mg per day, more preferably 140 to160 mg per day and most preferably 150 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 110 to175 mg per day, from 110 to 160 mg per day or from 110 to 150 mg perday. Also disclosed are doses from 125 to 160 mg or 140 to 175 mg perday. Further preferred ranges are 145 to 155 mg per day. According to amore preferred aspect, these dosages are applied once a day.

At present, the dosage of macitentan for use in the treatment of PAH is10 mg per day. Patients obtaining this dosage may receive an immediatedose escalation to 75 mg per day or to 150 mg per day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (h),wherein the dosage of macitentan is escalated from 10 mg once per day,preferably for 15 to 45 days; followed by 25 to 50 mg per day,preferably 37.5 mg once per day, preferably for 15 to 45 days; andoptionally followed by 60 to 90 mg per day, preferably by 75 mg once perday or 37.5 mg twice per day. It is to be understood that any escalationto a higher dose may be followed by return to the lower dose in case thehigher dose is not tolerated.

Therein, the term “15 to 45 days” means preferably 20 to 40 days, morepreferably 21 to 35 days, and most preferably 28 to 30 days, i.e. aboutone month.

Moreover, the phrase “followed by 25 to 50 mg per day” means preferably,the dosage is 30 to 45 mg per day, more preferably 35 to 40 mg per dayand most preferably 37.5 mg per day. It is to be understood that each ofthe lower limits disclosed may be combined with each of the upperlimits, i.e. the dosage could also be from 25 to 45 mg per day, or from25 to 40 mg per day. Also disclosed are doses from 30 to 50 mg, or 30 to40 mg per day. Further preferred ranges are 36 to 39 mg per day.

Moreover, the phrase “followed by 60 to 90 mg per day” means preferably,the dosage is 65 to 85 mg per day, more preferably the dosage is 70 to80 mg per day and most preferably the dosage is 75 mg per day. It is tobe understood that each of the lower limits disclosed above may becombined with each of the upper limits, i.e. the dosage could also befrom 60 to 85 mg, from 60 to 80 mg, or from 60 to 75 mg per day. Alsodisclosed are dosages from 65 to 90 mg, or 65 to 75 mg per day. Furtherpreferred ranges are 72 to 78 mg per day, or 36 to 39 mg twice per day.

According to a more preferred aspect, these dosages are applied once aday.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to aspect (h),wherein the dosage of macitentan is escalated from 10 mg once per day,preferably for 15 to 45 days; followed by 25 to 50 mg per day,preferably 37.5 mg once per day, preferably for 15 to 45 days;optionally followed by 60 to 90 mg per day, preferably by 75 mg once perday or 37.5 mg twice per day, preferably for 15 to 45 days; optionallyfollowed by 110 to 200 mg per day, preferably 150 mg per day.

The phrase “optionally followed by 110 to 200 mg per day” meanspreferably, the dosage is 125 to 175 mg per day, more preferably 140 to160 mg per day and most preferably 150 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 110 to175 mg per day, from 110 to 160 mg per day or from 110 to 150 mg perday. Also disclosed are doses from 125 to 160 mg or 140 to 175 mg perday. Further preferred ranges are 145 to 155 mg per day. According to amore preferred aspect, these dosages are applied once a day.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

(k) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to aspect (i),wherein the dosage of macitentan is escalated from 10 mg once per day,preferably for 15 to 45 days; followed by 60 to 90 mg per day,preferably by 75 mg once per day or 37.5 mg twice per day.

Therein, the term “15 to 45 days” means preferably 20 to 40 days, morepreferably 21 to 35 days, and most preferably 28 to 30 days, i.e. aboutone month.

The phrase “followed by 60 to 90 mg per day” means preferably, thedosage is 65 to 85 mg per day, more preferably the dosage is 70 to 80 mgper day and most preferably the dosage is 75 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 60 to85 mg, from 60 to 80 mg, or from 60 to 75 mg per day. Also disclosed aredosages from 65 to 90 mg, or 65 to 75 mg per day. Further preferredranges are 72 to 78 mg per day, or 36 to 39 mg twice per day.

A further aspect of the present invention relates to macitentan for usein the treatment and/or prevention of PAH according to (i), wherein thedosage of macitentan is escalated from 10 mg once per day, preferablyfor 15 to 45 days; followed by 60 to 90 mg per day, preferably by 75 mgonce per day or 37.5 mg twice per day, preferably for 15 to 45 days;optionally followed by 110 to 200 mg per day, preferably 150 mg per day.The phrase “optionally followed by 110 to 200 mg per day” meanspreferably, the dosage is 125 to 175 mg per day, more preferably 140 to160 mg per day and most preferably 150 mg per day. It is to beunderstood that each of the lower limits disclosed above may be combinedwith each of the upper limits, i.e. the dosage could also be from 110 to175 mg per day, from 110 to 160 mg per day or from 110 to 150 mg perday. Also disclosed are doses from 125 to 160 mg or 140 to 175 mg perday. Further preferred ranges are 145 to 155 mg per day.

According to a more preferred aspect, these dosages are applied once aday.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

(l) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to any one ofaspects (a) to (d), wherein the dosage of macitentan is escalated to 25to 50 mg per day, preferably 37.5 mg per day; preferably for 15 to 45days; optionally followed by 60 to 90 mg per day, preferably by 75 mgper day; provided that the patient is already treated with an endothelinreceptor antagonist preferably selected from bosentan and ambrisentan.It is to be understood that any escalation to a higher dose may befollowed by return to the lower dose in case the higher dose is nottolerated.

Therein, the term “15 to 45 days” means preferably 20 to 40 days, morepreferably 21 to 35 days, and most preferably 28 to 30 days, i.e. aboutone month.

Moreover, the phrase “followed by 25 to 50 mg per day” means preferably,the dosage is 30 to 45 mg per day, more preferably 35 to 40 mg per dayand most preferably 37.5 mg per day. It is to be understood that each ofthe lower limits disclosed may be combined with each of the upperlimits, i.e. the dosage could also be from 25 to 45 mg per day, or from25 to 40 mg per day. Also disclosed are doses from 30 to 50 mg, or 30 to40 mg per day. Further preferred ranges are 36 to 39 mg per day.

Moreover, the phrase “followed by 60 to 90 mg per day” means preferably,the dosage is 65 to 85 mg per day, more preferably the dosage is 70 to80 mg per day and most preferably the dosage is 75 mg per day. It is tobe understood that each of the lower limits disclosed above may becombined with each of the upper limits, i.e. the dosage could also befrom 60 to 85 mg, from 60 to 80 mg, or from 60 to 75 mg per day. Alsodisclosed are dosages from 65 to 90 mg, or 65 to 75 mg per day. Furtherpreferred ranges are 72 to 78 mg per day, or 36 to 39 mg twice per day.

It is to be understood, that optionally, the dosage of macitentan can befurther raised from 110 to 200 mg per day. The dosage is therebyescalated as in aspect (i), (j) or (k).

According to a more preferred aspect, these dosages are applied once aday.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

(m) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to any one ofaspects (a) to (c), wherein the dosage of macitentan is 60 to 90 mg perday, preferably 75 mg per day; provided that the patient is alreadytreated with an endothelin receptor antagonist preferably selected frombosentan, and ambrisentan.

The phrase “60 to 90 mg per day” means preferably, the dosage is 65 to85 mg per day, more preferably the dosage is 70 to 80 mg per day andmost preferably the dosage is 75 mg per day. It is to be understood thateach of the lower limits disclosed above may be combined with each ofthe upper limits, i.e. the dosage could also be from 60 to 85 mg, from60 to 80 mg, or from 60 to 75 mg per day. Also disclosed are dosagesfrom 65 to 90 mg, or 65 to 75 mg per day. Further preferred ranges are72 to 78 mg per day, or 36 to 39 mg twice per day.

It is to be understood, that optionally, the dosage of macitentan can befurther raised from 110 to 200 mg per day. The dosage is therebyescalated as in aspect (i), (j) or (k).

According to a more preferred aspect, these dosages are applied once aday.

In a preferred aspect, these dosages relate to macitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

(n) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to any one ofaspects (a) to (m), wherein macitentan is combined with a PDE5 inhibitorand/or a prostacyclin analogue, and/or a prostacyclin receptor agonistand/or a soluble guanylate cyclase stimulator.

Inhibition of the cyclic guanosine monophosphate (cGMP) degrading enzymephosphodiesterase type 5 results in vasodilation through the NO/cGMPpathway at sites expressing this enzyme. Since the pulmonary vasculaturecontains substantial amounts of phosphodiesterase type 5, the potentialclinical benefit of phosphodiesterase type 5 inhibitors (PDE5 is) hasbeen investigated in PAH. In addition, PDE5 is exert antiproliferativeeffects (ESC/ERS Guidelines; European Heart Journal (2016), 37, 67-119).

Prostacyclin is produced predominantly by endothelial cells and inducespotent vasodilation of all vascular beds. This compound is the mostpotent endogenous inhibitor of platelet aggregation and also appears tohave both cytoprotective and antiproliferative activities. Dysregulationof the prostacyclin metabolic pathways has been shown in patients withPAH as assessed by a reduction of prostacyclin synthase expression inthe pulmonary arteries and of prostacyclin urinary metabolites. Theclinical use of prostacyclin in patients with PAH has been extended bythe synthesis of stable analogues that possess different pharmacokineticproperties but share qualitatively similar pharmacodynamic effects(ESC/ERS Guidelines; European Heart Journal (2016), 37, 67-119).

No Drug-Drug Interaction has been observed for macitentan and its activemetabolite, ACT-132577 so far.

For example, macitentan 10 mg per day o.d. has not shown any effect onthe pharmacokinetics of 1 mg rosuvastatin, which suggests that BCRPtransporters have not been inhibited. BCRP is an efflux pump located inthe gut, liver canalicular membrane, and kidney, and is exposed tointracellular drug concentrations in the liver and the kidney.

Macitentan and ACT-132577 activated human PXR with EC₅₀ values of 1.1 to1.2 μM and 7.2 to 8.7 μM, respectively. In human hepatocytes, bothcompounds elicited concentration-dependent increases in CYP3A4 mRNA andenzyme activity.

Predicted peak plasma concentrations of macitentan and ACT-132577 in PAHpatients at 75 mg per day dose are expected to be around 5 μM and 14 μM,respectively, based on the PK Sub-study and assuming dose linearity.Taking into account the high degree of protein binding, free plasmaconcentrations are expected to be in the range of 0.02 μM to 0.07 μM formacitentan and ACT-132577, respectively. It is not likely that theseunbound concentrations of macitentan and ACT-132577 result in anyinhibition of BCRP in the liver or kidney or induction of CYP3A4 enzymein the liver.

Therefore, the dosage of macitentan may be 60 to 90 mg per day in aspect(n). Preferably, the dosage is 65 to 85 mg per day, more preferably thedosage is 70 to 80 mg per day and most preferably the dosage is 75 mgper day. It is to be understood that each of the lower limits disclosedabove may be combined with each of the upper limits, i.e. the dosagecould also be from 60 to 85 mg, from 60 to 80 mg, or from 60 to 75 mgper day. Also disclosed are dosages from 65 to 90 mg, or 65 to 75 mg perday. A further preferred dosage range is 72 to 78 mg per day.

Further, the dosage of macitentan may be escalated from 10 mg per day,followed by 25 to 50 mg per day, preferably 37.5 mg per day, followed by60 to 90 mg per day, preferably 75 mg per day, optionally followed by100 to 200 mg per day, preferably 150 mg per day.

In a preferred aspect, these combinations relate to macitentan for usein the treatment and/or prevention of mild or moderate PAH, preferablymoderate PAH.

(o) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to aspect (n),wherein the PDE5 inhibitor is selected from sildenafil, tadalafil,vardenafil, and udenafil; the prostacyclin analogue is selected fromepoprostenol, treprostinil, iloprost, and beraprost; the prostacyclinreceptor agonist is selected from selexipag and ralinepag; and thesoluble guanylate cyclase stimulator is selected from riociguat andvericiguat.

Therein, macitentan has a dosage or dosage regimen according to any oneof aspects (a) to (l) and (n). In a preferred aspect, these dosagesrelate to macitentan for use in the treatment and/or prevention of mildor moderate PAH.

In a preferred aspect, these combinations relate to macitentan for usein the treatment and/or prevention of mild or moderate PAH, preferablymoderate PAH.

(p) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to aspect (n) or(o), wherein macitentan is combined with tadalafil and/or selexipag orralinepag. Preferably, macitentan is combined with tadalafil and/orselexipag.

Therein, macitentan has a dosage or dosage regimen according to any oneof aspects (a) to (k) and (n). In a preferred aspect, these dosagesrelate to macitentan for use in the treatment and/or prevention of mildor moderate PAH.

In a preferred aspect, these combinations relate to macitentan for usein the treatment and/or prevention of mild or moderate PAH, preferablymoderate PAH.

(q) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to aspect (p),wherein tadalafil, if applicable, has a dose of 20 to 40 mg per day,preferably 40 mg per day, selexipag, if applicable, has a dose of 0.2 to1.6 mg twice per day, and ralinepag, if applicable, has a dose of 0.05to 1.45 mg per day.

Therein, macitentan has a dosage or dosage regimen according to any oneof aspects (a) to (k) and (n). In a preferred aspect, these dosagesrelate to macitentan for use in the treatment and/or prevention of mildor moderate PAH.

In a preferred aspect, these combinations relate to macitentan for usein the treatment and/or prevention of mild or moderate PAH, preferablymoderate PAH.

(r) A further aspect of the present invention relates to apharmaceutical composition for use in the treatment of PAH comprisingmacitentan and at least a pharmaceutically acceptable excipient,containing macitentan in an amount of more than 20 mg to equal to orless than 300 mg, for example, more than 20 mg to less than 250 mg,preferably 37.5 mg, 75 mg or 150 mg, more preferably 37.5 mg or 75 mg,most preferably 75 mg.

It is to be understood that macitentan may have a dosage according toany one of the daily dosages of aspects (a) to (e).

In a preferred aspect, the pharmaceutical composition is for use in thetreatment and/or prevention of mild or moderate PAH.

(s) A further aspect of the present invention relates to thepharmaceutical composition according to aspect (r), which comprises

i) macitentan in a total amount of 10 to 50% in weight based on thetotal weight of the pharmaceutical composition,

ii) a filler, consisting of lactose monohydrate with microcrystallinecellulose, in a total amount of 10 to 85% in weight based on the totalweight of the pharmaceutical composition,

iii) a disintegrant, consisting of sodium starch glycolate or acombination of sodium starch glycolate and polyvinylpyrrolidone, in atotal amount of 1 to 10% in weight based on the total weight of thepharmaceutical composition,

iv) a surfactant, consisting of a polysorbate, in a total amount of 0.1to 1% in weight based on the total weight of the pharmaceuticalcomposition, and

v) a lubricant, consisting of magnesium stearate, in a total amount of0.05 to 5% in weight based on the total weight of the pharmaceuticalcomposition.

(t) A further aspect of the present invention relates to thepharmaceutical composition according to aspect (r) or (s), which is inthe form of a capsule or a tablet (in particular in the form of atablet, notably a tablet containing 75 mg of macitentan).

(u) A further aspect of the present invention relates to macitentan foruse in the treatment and/or prevention of PAH according to any one ofaspects (a) to (q), wherein the treatment and/or prevention means thereduction of morbidity and/or mortality risk of PAH. That is, thisaspect of the present invention relates to macitentan for use inreducing morbidity and/or mortality risk of PAH, in which macitentan isused in a manner according to any one of aspects (a) to (q).

The reduction of morbidity and/or mortality risk of PAH may be evaluatedas the reduction of the composite morbidity/mortality risk, for example,by time to first clinical worsening up to 7 days after EOT (End ofTreatment), defined as time from baseline to the first of the followingevents (the primary endpoint):

-   -   Death (all-cause mortality);    -   Pulmonary hypertension related hospitalization (including for        worsening of PAH, atrial septostomy, lung transplantation with        or without heart transplantation, or initiation of parenteral        prostacyclins);    -   Worsening of PAH resulting in initiation of parenteral        prostanoid therapy;    -   Pulmonary hypertension related disease progression, defined as:        -   For functional class II and III patients at baseline (both            criteria have to be satisfied):            -   More than 15% decrease in 6-minute walk distance (6MWD)                from baseline, confirmed by two 6MWD tests performed on                separate days within 2 weeks of each other;            -   Initiation of additional PAH therapy or Worsening of WHO                Functional Class;    -   For functional class IV patients at baseline (both criteria have        to be satisfied):        -   More than 15% decrease in 6MWD from baseline, confirmed by            two 6MWD tests performed on separate days within 2 weeks of            each other;        -   Initiation of additional PAH therapy.

Alternatively, the reduction of morbidity and/or mortality risk of PAHmay be evaluated separately.

The above evaluation may be made for example by the following schedule:

i) Run-in period (for example 4 weeks) with the dosage of macitentan of10 mg per day;

ii) Titration period (for example 4 weeks) with the dosage of macitentanof 37.5 mg per day;

iii) Maintenance period with the dosage of macitentan of 75 mg per day.

The above evaluation may be made for example by a double blind test withthe control group receiving the dosage of macitentan of 10 mg per day inthe titration and maintenance period.

For reducing the morbidity and/or mortality risk of PAH, the dosage ofmacitentan may be 60 to 90 mg per day. Preferably, the dosage is 65 to85 mg per day, more preferably the dosage is 70 to 80 mg per day andmost preferably the dosage is 75 mg per day. It is to be understood thateach of the lower limits disclosed above may be combined with each ofthe upper limits, i.e. the dosage could also be from 60 to 85 mg, from60 to 80 mg, or from 60 to 75 mg per day. Also disclosed are dosagesfrom 65 to 90 mg, or 65 to 75 mg per day. A further preferred dosagerange is 72 to 78 mg per day.

Further, the dosage of macitentan may be escalated from 10 mg per day,followed by 25 to 50 mg per day, preferably 37.5 mg per day, followed by60 to 90 mg per day, preferably 75 mg per day, optionally followed by100 to 200 mg per day, preferably 150 mg per day.

It is to be understood that all disclosed aspects are to be regarded asdisclosed also in the form of macitentan for the manufacture of amedicament for the uses according to any one of aspects (a) to (q) and(u):

(a′) One aspect of the present invention relates to macitentan for themanufacture of a medicament for use in the treatment and/or preventionof pulmonary arterial hypertension (PAH) in human, wherein the dosage ofmacitentan is more than 20 mg per day to equal to or less than 300 mgper day, for example, more than 20 mg per day to less than 250 mg perday. It is to be understood that the disclosure of aspect (a) appliesanalogously.

(b′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of pulmonary arterial hypertension (PAH) according to aspect(a′), wherein the PAH is mild or moderate PAH, preferably moderate PAH.It is to be understood that the disclosure of aspect (b) appliesanalogously.

(c′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is 60 to 90 mg per day, preferably 65 to 85 mg per day,more preferably 70 to 80 mg per day and most preferably 75 mg per day.It is to be understood that the disclosure of aspect (c) appliesanalogously.

(d′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is 25 to 50 mg per day, preferably 30 to 45 mg per day,more preferably 35 to 40 mg per day and most preferably 37.5 mg per day.It is to be understood that the disclosure of aspect (d) appliesanalogously.

(e′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is 110 to 200 mg per day, preferably 125 to 175 mg perday, more preferably 140 to 160 mg per day and most preferably 150 mgper day. It is to be understood that the disclosure of aspect (e)applies analogously.

(f′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is 60 to 90 mg twice per day, preferably 65 to 85 mg twiceper day, more preferably 70 to 80 mg twice per day and most preferably75 mg twice per day. It is to be understood that the disclosure ofaspect (f) applies analogously.

(g′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is 25 to 50 mg twice per day, preferably 30 to 45 mg twiceper day, more preferably 35 to 40 mg twice per day and most preferably37.5 mg twice per day. It is to be understood that the disclosure ofaspect (g) applies analogously.

(h′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a′) or (b′), wherein the dosageof macitentan is escalated from 10 mg per day, followed by 25 to 50 mgper day, preferably 37.5 mg per day, and optionally followed by 60 to 90mg per day, preferably 75 mg per day. It is to be understood that thedisclosure of aspect (h) applies analogously.

(i′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (a) or (b), wherein the dosage ofmacitentan is escalated from 10 mg per day, followed by 60 to 90 mg perday, preferably 75 mg once per day or 37.5 mg twice a day. It is to beunderstood that the disclosure of aspect (i) applies analogously.

(j′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (h′), wherein the dosage ofmacitentan is escalated from 10 mg once per day, preferably for 15 to 45days; followed by 25 to 50 mg per day, preferably 37.5 mg once per day,preferably for 15 to 45 days; and optionally followed by 60 to 90 mg perday, preferably by 75 mg once per day or 37.5 mg twice per day. It is tobe understood that the disclosure of aspect (j) applies analogously.

(k′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (i′), wherein the dosage ofmacitentan is escalated from 10 mg once per day, preferably for 15 to 45days; followed by 60 to 90 mg per day, preferably by 75 mg once per dayor 37.5 mg twice per day. It is to be understood that the disclosure ofaspect (k) applies analogously.

(l′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to any one of aspects (a′) to (d′), whereinthe dosage of macitentan is escalated from 25 to 50 mg per day,preferably 37.5 mg per day, preferably for 15 to 45 days; optionallyfollowed by 60 to 90 mg per day, preferably by 75 mg per day; providedthat the patient is already treated with an endothelin receptorantagonist preferably selected from bosentan and ambrisentan. It is tobe understood that the disclosure of aspect (l) applies analogously.

(m′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to any one of aspects (a′) to (c′), whereinthe dosage of macitentan is 60 to 90 mg per day, preferably 75 mg perday; provided that the patient is already treated with an endothelinreceptor antagonist preferably selected from bosentan and ambrisentan.It is to be understood that the disclosure of aspect (m) appliesanalogously.

(n′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to any one of aspects (a′) to (m′), whereinmacitentan is combined with a PDE5 inhibitor and/or a prostacyclinanalogue, and/or a prostacyclin receptor agonist and/or a solubleguanylate cyclase stimulator. It is to be understood that the disclosureof aspect (n) applies analogously.

(o′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (n′), wherein the PDE5 inhibitoris selected from sildenafil, tadalafil, vardenafil, and udenafil; theprostacyclin analogue is selected from epoprostenol, treprostinil,iloprost, and beraprost; the prostacyclin receptor agonist is selectedfrom selexipag and ralinepag; and the soluble guanylate cyclasestimulator is selected from riociguat and vericiguat. It is to beunderstood that the disclosure of aspect (o) applies analogously.

(p′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (n) or (o′), wherein macitentan iscombined with tadalafil and/or selexipag or ralinepag, preferablytadalafil and/or selexipag. It is to be understood that the disclosureof aspect (p) applies analogously.

(q′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to aspect (p′), wherein tadalafil, ifapplicable, has a dose of 20 to 40 mg per day, preferably 40 mg per day,selexipag, if applicable, has a dose of 0.2 to 1.6 mg twice per day andralinepag, if applicable, has a dose of 0.05 to 1.45 mg per day. It isto be understood that the disclosure of aspect (q) applies analogously.

(u′) Another aspect of the present invention relates to macitentan forthe manufacture of a medicament for use in the treatment and/orprevention of PAH according to any one of aspects (a′) to (q′), whereinthe treatment and/or prevention means the reduction of morbidity and/ormortality risk of PAH. That is, this aspect of the present inventionrelates to macitentan for the manufacture of a medicament in reducingmorbidity and/or mortality risk of PAH, in which macitentan isadministered in a manner according to any one of aspects (a′) to (q′).It is to be understood that the disclosure of aspect (u) appliesanalogously.

It is to be understood that the comments and details of aspects (a) to(q) and (u) also apply to aspects (a′) to (q′) and (u′).

Moreover, it is to be understood that all disclosed aspects (a) to (q)and (u) are to be regarded as disclosed also in the form of a method oftreatment:

(a″) One aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH) inhuman, said method comprising administering macitentan in a dosage ofmore than 20 mg per day to equal to or less than 300 mg per day, forexample, more than 20 mg per day to less than 250 mg per day to asubject in need thereof. It is to be understood that the disclosure ofaspect (a) applies analogously.

(b″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″), wherein the PAH is mild or moderate PAH,preferably moderate PAH. It is to be understood that the disclosure ofaspect (b) applies analogously.

(c″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan is 60to 90 mg per day, preferably 65 to 85 mg per day, more preferably 70 to80 mg per day and most preferably 75 mg per day. It is to be understoodthat the disclosure of aspect (c) applies analogously.

(d″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan is 25to 50 mg per day, preferably 30 to 45 mg per day, more preferably 35 to40 mg per day and most preferably 37.5 mg per day. It is to beunderstood that the disclosure of aspect (d) applies analogously.

(e″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan is110 to 200 mg per day, preferably 125 to 175 mg per day, more preferably140 to 160 mg per day and most preferably 150 mg per day. It is to beunderstood that the disclosure of aspect (e) applies analogously.

(f″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan is 60to 90 mg twice per day, preferably 65 to 85 mg twice per day, morepreferably 70 to 80 mg twice per day and most preferably 75 mg twice perday. It is to be understood that the disclosure of aspect (f) appliesanalogously.

(g″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan is 25to 50 mg twice per day, preferably 30 to 45 mg twice per day, morepreferably 35 to 40 mg twice per day and most preferably 37.5 mg twiceper day. It is to be understood that the disclosure of aspect (g)applies analogously.

(h″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan isescalated from 10 mg per day, followed by 25 to 50 mg per day,preferably 37.5 mg per day, and optionally followed by 60 to 90 mg perday, preferably 75 mg per day. It is to be understood that thedisclosure of aspect (h) applies analogously.

(i″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (a″) or (b″), wherein the dosage of macitentan isescalated from 10 mg per day, followed by 60 to 90 mg per day,preferably 75 mg once per day or 37.5 mg twice a day. It is to beunderstood that the disclosure of aspect (i) applies analogously.

(j″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (h″), wherein the dosage of macitentan is escalatedfrom 10 mg once per day, preferably for 15 to 45 days; followed by 25 to50 mg per day, preferably 37.5 mg once per day, preferably for 15 to 45days; and optionally followed by 60 to 90 mg per day, preferably by 75mg once per day or 37.5 mg twice per day. It is to be understood thatthe disclosure of aspect (j) applies analogously.

(k″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (i″), wherein the dosage of macitentan is escalatedfrom 10 mg once per day, preferably for 15 to 45 days; followed by 60 to90 mg per day, preferably by 75 mg once per day or 37.5 mg twice perday. It is to be understood that the disclosure of aspect (k) appliesanalogously.

(l″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to any one of aspects (a″) to (d″), wherein the dosage ofmacitentan is escalated from 25 to 50 mg per day, preferably 37.5 mg perday, preferably for 15 to 45 days; optionally followed by 60 to 90 mgper day, preferably by 75 mg per day; provided that the patient isalready treated with an endothelin receptor antagonist preferablyselected from bosentan and ambrisentan. It is to be understood that thedisclosure of aspect (l) applies analogously.

(m″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to any one of aspects (a″) to (c″), wherein the dosage ofmacitentan is 60 to 90 mg per day, preferably 75 mg per day; providedthat the patient is already treated with an endothelin receptorantagonist preferably selected from bosentan and ambrisentan. It is tobe understood that the disclosure of aspect (m) applies analogously.

(n″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to any one of aspects (a″) to (m″), wherein macitentan iscombined with a PDE5 inhibitor and/or a prostacyclin analogue, and/or aprostacyclin receptor agonist and/or a soluble guanylate cyclasestimulator. It is to be understood that the disclosure of aspect (n)applies analogously.

(o″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (n″), wherein the PDE5 inhibitor is selected fromsildenafil, tadalafil, vardenafil, and udenafil; the prostacyclinanalogue is selected from epoprostenol, treprostinil, iloprost, andberaprost; the prostacyclin receptor agonist is selected from selexipagand ralinepag; and the soluble guanylate cyclase stimulator is selectedfrom riociguat and vericiguat. It is to be understood that thedisclosure of aspect (o) applies analogously.

(p″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (n″) or (o″), wherein macitentan is combined withtadalafil and/or selexipag or ralinepag, preferably tadalafil and/orselexipag. It is to be understood that the disclosure of aspect (p)applies analogously.

(q″) Another aspect of the present invention relates to a method oftreatment and/or prevention of pulmonary arterial hypertension (PAH)according to aspect (p″), wherein tadalafil, if applicable, has a doseof 20 to 40 mg per day, preferably 40 mg per day, selexipag, ifapplicable, has a dose of 0.2 to 1.6 mg twice per day and ralinepag, ifapplicable, has a dose of 0.05 to 1.45 mg per day. It is to beunderstood that the disclosure of aspect (q) applies analogously.

(u″) Another aspect of the present invention relates to a method oftreatment and/or prevention of PAH according to any one of aspects (a″)to (q″), wherein the treatment and/or prevention means the reduction ofmorbidity and/or mortality risk of PAH. That is, this aspect of thepresent invention relates to a method of reducing morbidity and/ormortality risk of PAH, in which macitentan is administered in a manneraccording to any one of aspects (a″) to (q″). It is to be understoodthat the disclosure of aspect (u) applies analogously.

It is to be understood that the comments and details of aspects (a) to(q) also apply to aspects (a″) to (q″) and (u″).

According to a further aspect of the present invention, in each of theabove-mentioned aspects, that is, in each of aspects (a) to (t) and (u),(a′) to (q′) and (u′) as well as (a″) to (q″) and (u″), macitentan canbe replaced by its active metabolite, known under the code nameACT-132577 and the International Non-proprietary Name aprocitentan,which has the chemical formula

whereby any weight amount of macitentan will be replaced a 5-fold weightamount of aprocitentan.

For example, taking aspect (c) of the invention described above, afurther aspect of the invention relates to aprocitentan for use in thetreatment and/or prevention of PAH according to aspect (a) or (b)wherein the weight amounts of macitentan aprocitentan will be replaced a5-fold weight amount of aprocitentan, wherein the dosage of aprocitentanis 300 to 450 mg per day. Preferably, the dosage of aprocitentan is 325to 425 mg per day, more preferably the dosage of aprocitentan is 350 to400 mg per day and most preferably the dosage of aprocitentan is 375 mgper day. It is to be understood that each of the lower limits disclosedabove may be combined with each of the upper limits, i.e. the dosage ofaprocitentan could also be from 300 to 425 mg, from 300 to 400 mg, orfrom 300 to 375 mg per day. Also disclosed are dosages of aprocitentanfrom 325 to 450 mg, or 325 to 375 mg per day. Further preferred rangesare 360 to 390 mg of aprocitentan per day. According to a more preferredaspect, these dosages of aprocitentan are applied once a day. In apreferred aspect, these dosages relate to aprocitentan for use in thetreatment and/or prevention of mild or moderate PAH, preferably moderatePAH.

Moreover, the following abbreviations are used throughout the presentspecification.

Abbreviations

-   APAH-CTD PAH associated with connective tissue disease-   APAH-PoPH PAH associated with porto-pulmonary hypertension-   aq. aqueous-   BNP brain natriuretic peptide-   BPM beats per minute-   CI cardiac index-   DLCO diffusing capacity of lung for CO (carbon monoxide)-   EDTA ethylenediaminetetraacetic acid-   ERA endothelin receptor antagonist-   ET endothelin-   FPAH familial PAH-   HR heart rate-   IgG immunoglobulin G-   K₂EDTA ethylenediaminetetraacetic acid dipotassium salt-   mPAP mean pulmonary artery pressure-   6MWD 6-minute walk distance-   NT-proBNP N-terminal pro-brain natriuretic peptide-   PAH pulmonary arterial hypertension-   PAOP pulmonary artery occlusion pressure, which is synonymous with    PAWP-   PAWP pulmonary capillary wedge pressure, which is synonymous with    PAOP-   PAP pulmonary artery pressure-   PBS phosphate buffered saline-   PD pharmacodynamics-   PDE5 cyclic guanosine 3′,5′-monophosphate (cGMP) phosphodiesterase    type 5-   PDE5 is PDE5 inhibitors-   PH pulmonary hypertension-   PK pharmacokinetics-   PVR pulmonary vascular resistance-   RAP right arterial pressure (sometimes also referred to as mRAP)-   RHC right heart catheterization-   SBP systolic systemic blood pressure-   SvO₂ mixed venous oxygen saturation-   Tris tris(hydroxymethyl)aminomethane-   WHO World Health Organization-   WHO FC World Health Organization Functional Class

EXPERIMENTAL PART

The following non-limitative examples illustrate the invention.

EXAMPLES

Effect of Macitentan on Decrease in Hemoglobin Concentration

Hemoglobin measurements were pooled from 3 Phase I clinical studies inhealthy volunteers:

Study AC-055-102: Investigation of the PK, PD, safety and tolerabilityof macitentan in male subjects (the study protocol is described in thefollowing publication: Sidharta et al., Safety, tolerability,pharmacokinetics, and pharmacodynamics of macitentan, an endothelinreceptor antagonist, in an ascending multiple-dose study in healthysubjects. J. Clin. Pharmacol. (2013), 53(11), 1131-1138)

Study AC-055-116: Investigation of the PK, PD, safety and tolerabilityof macitentan in male Japanese subjects (the study protocol is describedin the following publication: Yokoyama et al., Tolerability, Safety,Pharmacokinetics, and Pharmacodynamics of Macitentan, a New EndothelinReceptor Antagonist, in Healthy Japanese Male Subjects. Rinshoyakuri/Japanese Journal of Clinical Pharmacology and Therapeutics(2016), 47, 143-150)

Study AC-055-117: Investigation of the PK, PD, safety and tolerabilityof macitentan in male Korean subjects (the study protocol is describedin the following publication: Ahn et al.,Pharmacokinetic-pharmacodynamic relationships of macitentan, a newendothelin receptor antagonist, after multiple dosing in healthy Koreansubjects, Am. J. Cardiovasc. Drugs (2014), 14(5), 377-385)

Hemoglobin concentrations measured in the morning of Day 11 ofmacitentan treatment and at baseline on Day −1 were used in theanalysis. Changes in hemoglobin concentrations compared to baseline wereregressed against the different dose levels of macitentan, includingplacebo.

An Emax curve with baseline was fitted and the following parameters wereestimated by nonlinear regression:

E0: Change in hemoglobin without macitentan

Emax: Maximum change in hemoglobin theoretically could be elicited bymacitentan

ED50: the dose resulting in 50% reduction of hemoglobin

The following formula was used:

Change in hemoglobin=E0+((Macitentan dose×Emax)/(Macitentan dose+ED50))

The resulting dose-response curve is shown in FIG. 1.

Based on the analysis, the maximum effect of macitentan on hemoglobindecrease would be around 1.23 g/dL and the effect of macitentan onhemoglobin decrease plateaus already at the 10 mg dose (see FIG. 1).Therefore, no clinically relevant decrease in hemoglobin is expectedabove a 10 mg dose of macitentan in humans.

What is claimed is:
 1. A method of administering macitentan, or apharmaceutically acceptable salt, solvate, hydrate, or morphologicalform thereof, to a human patient having pulmonary arterial hypertension(PAH) and in need of treatment thereof, comprising administering themacitentan to the patient at a dosage of 10 mg per day for a firstperiod of time; followed by administering the macitentan to the patientat a dosage of 25 mg to 50 mg per day for a second period of time; andfollowed by administering the macitentan to the patient at a dosage of60 mg to 90 mg per day for a maintenance period of time.
 2. The methodof claim 1, wherein the first period of time is 15 to 45 days.
 3. Themethod of claim 2, wherein the first period of time is 15 days.
 4. Themethod of claim 2, wherein the second period of time is 15 to 45 days.5. The method of claim 3, wherein the second period of time is 15 days.6. The method of claim 4, wherein the macitentan is administered at adosage of 70 mg to 80 mg per day for the maintenance period of time. 7.The method of claim 6, wherein the macitentan is administered at adosage of 35 mg to 40 mg per day for the second period of time.
 8. Themethod of claim 5, wherein the macitentan is administered at a dosage of70 mg to 80 mg per day for the maintenance period of time.
 9. The methodof claim 8, wherein the macitentan is administered at a dosage of 35 mgto 40 mg per day for the second period of time.
 10. The method of claim4, wherein the macitentan is administered at a dosage of 75 mg per dayfor the maintenance period of time.
 11. The method of claim 10, whereinthe macitentan is administered at a dosage of 37.5 mg twice per day forthe maintenance period of time.
 12. The method of claim 10, wherein themacitentan is administered at a dosage of 37.5 mg per day for the secondperiod of time.
 13. The method of claim 5, wherein the macitentan isadministered at a dosage of 75 mg per day for the maintenance period oftime.
 14. The method of claim 13, wherein the macitentan is administeredat a dosage of 37.5 mg twice per day for the maintenance period of time.15. The method of claim 13, wherein the macitentan is administered at adosage of 37.5 mg per day for the second period of time.
 16. The methodof claim 1, wherein the method reduces a morbidity risk, a mortalityrisk, or both, of the PAH.
 17. The method of claim 1, wherein the PAH ismild or moderate PAH.
 18. The method of claim 17, wherein the PAH ismoderate PAH.
 19. The method of claim 1, further comprisingadministering to the patient a PDE5 inhibitor, a prostacyclin analogue,a prostacyclin receptor agonist, or a soluble guanylate cyclasestimulator, or a combination thereof.
 20. The method of claim 19,wherein the PDE5 inhibitor is sildenafil, tadalafil, vardenafil, orudenafil; the prostacyclin analogue is epoprostenol, treprostinil,iloprost, or beraprost; the prostacyclin receptor agonist is selexipagor ralinepag; and the soluble guanylate cyclase stimulator is riociguator vericiguat.
 21. The method of claim 1, further comprisingadministering to the patient tadalafil, selexipag, or ralinepag, or acombination thereof.
 22. The method of claim 21, wherein the tadalafilis administered in a dose of 20 to 40 mg per day, the selexipag isadministered in a dose of 0.2 to 1.6 mg twice per day, and ralinepag isadministered in a dose of 0.05 mg to 1.45 mg per day.
 23. The method ofclaim 22, wherein the dose of tadalafil is 40 mg per day.
 24. The methodof claim 1, further comprising administering to the patient tadalafil orselexipag, or combinations thereof.